The PI3K-AKT pathway is hyperactivated in many human cancers, including renal cell carcinoma (RCC), and several drugs to inhibit this pathway are currently tested in various pre-clinical or clinical trials. However, it has been shown that PIK or AKT inhibition results in the relief of feedback regulation and activation of other oncogenic signaling pathways, which likely will limit the clinical utilization of these inhibitors as a singl agent in cancer treatment. In addition, only a fraction of cancer patients will likely respond positively to PI3K or AKT inhibitors, and it is unclear which patients will benefit most. Our long-term goal is to understand the PI3K-AKT signaling in the context of drug response and to translate such discoveries into meaningful clinical applications. The objective of this application is to study the roles of FoxO-Rictor signaling axis we identified in renal cancer treatment by PI3K or AKT inhibition. Our extensive preliminary data support the central hypothesis of our proposal that activation of FoxO mediates PI3K or AKT inhibition-directed reactivation of AKT by upregulating Rictor expression and promoting AKT Ser473 phosphorylation, which eventually will limit the impact of the PI3K or AKT inhibitor in renal cancer treatment. In this proposal, we will employ multi-disciplinary approaches, including detailed biochemical mechanistic studies, sophisticated genetically engineered mouse models, and analysis of renal cancer patient samples, to study FoxO-Rictor signaling axis in renal cancer development and treatment. The rationale for the proposed research is that our proposed studies will advance our understanding of PI3K-AKT inhibition-mediated feedback, and will provide important insight for the development of novel therapeutic strategies or biomarkers targeting PI3K-AKT pathway in renal cancer treatment. Our proposal is highly innovative, because it focuses on a previously unexplored mechanism that fills in the current gap in renal cancer treatment. Our proposed studies will have significant impact on both understanding the fundamental mechanisms of feedback regulation and manipulating FoxO-Rictor pathway clinically in the stratification and treatment of cancer patients.